Thiazolidinediones (TZDs) are a group of insulin-sensitizing drugs useful in the treatment and possibly in the prevention of type 2 diabetes mellitus. However, approximately 1/3 of individuals treated with TZDs show little or no clinical response. Responsiveness cannot be predicted from simple clinical parameters. Therefore, insight into the genetic mechanisms governing responsiveness will further rational prescription practices and may inform the development of new drugs. The purpose of the proposed research is to uncover predictors of response by administering a TZD to pre-diabetic individuals, defining the pathways governing clinical response, and locating crucial variants in the implicated genes. As an extension of our ongoing Pharmacogenomics of PPAR-gamma project, the Specific Aims of the proposed research are threefold. (1) First, we will characterize extensively the response of 75 individuals to 3 months of treatment with the TZD rosiglitazone. This characterization, which will be performed identically before and after treatment, focuses on insulin sensitivity, mechanistic precursors of clinical response observed in fat and muscle tissue samples, and gene expression profiles from these tissues obtained by microarray analysis. (2) Once we have identified the pathways whose regulation is correlated with TZD response, we will define sequence variation and haplotype structure of 100 candidate genes in these pathways. (3) Lastly, we will determine which sequence variants influence TZD response through association analysis of SNPs/haplotypes in our population and other populations treated with a TZD (Diabetes Prevention Program and TRIPOD/PI POD). The proposed studies will provide important insights into the mechanisms of action and determinants of responsiveness to a widely prescribed diabetes medication, as well as into insulin resistance in general. Insulin resistance is a central element of the metabolic syndrome, a constellation of adverse health factors that affects one in five adult Americans.